Multimodal MRI and multiomics reveal high-risk neurophenotype in brain-gut circuits as therapeutic target for Crohn's disease
Xuehua Li , Ruonan Zhang , Xiaodi Shen , Shaochun Lin , Chuhuai Wang , Weikai Zheng , Weimiao Kong , Zihao Lin , Rongchang Li , Caiguang Liu , Xin Cao , Li Huang , Weitao He , Jinjiang Lin , Haijie Wang , Zhoulei Li , Marietta Iacucci , Subrata Ghosh , Zhenpeng Peng , Canhui Sun , Minhu Chen , Guang Yang , Yejun Wang , Ren Mao , Shi-Ting Feng
Interdisciplinary Medicine ›› 2026, Vol. 4 ›› Issue (4) : e70122
The brain-gut axis shapes Crohn's disease (CD) pathogenesis, yet CD-associated neurophenotypes lack defined clinical and mechanistic significance. This work aimed to define these neurophenotypes, assess their prognostic impact, elucidate neurophenotype-driven progression mechanisms using multi-omics, and validate their therapeutic potential in vivo. 109 CD patients were prospectively recruited from two centers and underwent baseline multimodal neuro-MRI, MR enterography, ileocolonoscopy, and fecal/blood sample collection. The neurophenotypes were characterized using a multimodal neuro-MRI model developed from 13 of 13,870 features. 83 patients were followed up for disease progression, with repeated brain-gut assessments. Multi-omics (fecal microbiome/metabolomics, serum metabolomics/neurotransmitters) were used to decode the mechanisms underlying neurophenotype-driven progression. Dextran sulfate sodium (DSS)-induced colitis mice with different neurophenotypes were treated with repeated transcranial magnetic stimulation (rTMS) to explore its therapeutic potential. Multimodal neuro-MRI accurately mapped CD-specific neural signatures, stratifying patients into high-risk (neurophenotype score ≥ 0.45) and low-risk neurophenotypes with robust cross-center validity (training cohort AUC = 0.842, test cohort AUC = 0.824). High-risk neurophenotype was identified as an independent predictor of accelerated disease progression (Hazard ratio = 15.46, p = 0.030), independent of intestinal inflammation. Integrated multi-omics revealed that the high-risk neurophenotype contributed to CD progression through microbial-metabolic-neurotransmitter networks where tryptophan emerged as the central regulatory hub. Serum tryptophan levels were negatively correlated with neurophenotype severity and intestinal disease progression. rTMS targeting high-risk neurophenotype in DSS-induced colitis mice elevated tryptophan levels and ameliorated intestinal disease activity. This study redefines the high-risk neurophenotype as a sustained pathogenic driver rather than a mere phenomenon, proposing brain-gut axis modulation as a promising therapeutic strategy distinct from conventional anti-inflammatory approaches.
Crohn's disease / intestinal disease progression / multimodal MRI / neurophenotype
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2026 The Author(s). Interdisciplinary Medicine published by Wiley-VCH GmbH on behalf of Nanfang Hospital, Southern Medical University.
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